In the systemic treatment of anaerobic infections a parenteral mode of administration is advantageous for patients who are seriously ill and for whom oral administration is not feasible or may be considered to be insufficiently incisive. Heretofore, a practical way of administering a parenteral dose of metronidazole has not been available since the solubility of metronidazole in an aqueous solution is only about 100 mg/10 ml and a practical dosage unit is in the 500-650 mg/10 ml range. Those skilled in the art recognize the practical advantages of a single injectable dose of below 5 ml as opposed to the large volume of solution which would be needed to administer a 500-650 mg dose of metronidazole in an aqueous solution.
Attempts have been made to improve the solubility of metronidazole in various ways as illustrated by the following examples:
British patent application No. 2,000,025 discloses a method of solubilizing metronidazole in water by mixing it with gentisic acid in a ratio of 1:4.
U.S. Pat. No. 4,032,645 describes solutions of metronidazole in water with N,N-dimethylacetamide/ethanol or propylene glycol/2,2-dimethyl-1,3-dioxolane-4-methanol as co-solvents.
However, these methods have two drawbacks: Firstly, the solubility of metronidazole is only augmented to 500-650 mg/10 ml and secondly both require large amounts of substances that are foreign to the human organism.
Another conceivable solution to the problem is to administer metronidazole in the form of a derivative which has the desired solubility and which, after parenteral administration, is cleaved by the organism to yield metronidazole. Such a derivative could be an ester prepared from a pharmacologically acceptable acid.
Several esters of metronidazole are known. U.S. Pat. No. 2,994,061 describes esters of metronidazole with mono- or di-carboxylic aliphatic or aromatic acids.
U.S. Pat. No. 3,696,116 describes esters of metronidazole with carbamic acid.
British Pat. No. 1,270,810 mentions 4-toluene-sulphonic acid ester of metronidazole as an intermediate product.
German Offenlegungsschrift No. 2,030,314 describes the ester of methane sulphonic acid with metronidazole.
Unfortunately all of these esters are even less soluble in water than metronidazole itself.
Half-esters of metronidazole with dicarboxylic acids are known from Belgian Pat. No. 619672. The sodium salt of the half-ester with succinic acid which is described therein has the required solubility in water. However, the cleavage of the ester in blood serum after parenteral administration is very slow and the compound itself is microbiologically inactive.
U.S. Pat. No. 4,160,827 describes the monoester of phosphoric acid with metronidazole. The salts of this ester with pharmacologically acceptable cations are very soluble in water.
Although this ester may turn out to be a clinically useful prodrug, published data indicate a rather slow rate of conversion to metronidazole in vivo. Furthermore, the bioavailability to rats of metronidazole occurring after administration of the phosphate ester is significantly lower than that obtained with metronidazole at the same dosage level, which indicates the excretion of some unchanged phosphate ester.
A third type of water-soluble ester derivatives is esters with an ionizable amino function in the acid portion. Various amino acid esters have previously been described as water-soluble bioreversible derivatives of drugs containing a hydroxy group, such as oxazepam and lorazepam (Nudelman et al.: J. Pharm. Sci. 63, 1880-1885 (1974)), hydrocortisone (Kawamura et al.: Yakugaku Zasshi 91, 863-870 (1971)) and a pyridazin-3-one derivative (Fogt et al.: J. Med. Chem. 23, 1445-1448 (1980)), but only sparse information is available on their hydrolysis under physiological conditions.
Amino acid esters with metronidazole have been unknown hitherto. However, it has now been found that aminocarboxylic acid esters with metronidazole are soluble in water and that acid addition salts thereof are very soluble in water. In most cases solutions containing more than 20% w/v of such acid addition salts can be obtained.
Table 1 shows the half-lives for the hydrolysis to metronidazole of a series of such metronidazole esters in 80% human plasma (pH 7.4) and in 0.05M phosphate buffer (pH 7.4) at 37.degree. C.
TABLE 1 ______________________________________ t.sub.1/2 in human t.sub.1/2 in buffer Ester plasma (min) (min) ______________________________________ N,N--Dimethylglycinate 12 250 Glycinate 41 115 N--Propylglycinate 8 90 3-Aminopropionate 207 315 3-Dimethylaminopropionate 46 52 4-Dimethylaminobutyrate 334 580 4-Methyl-1-piperazinoacetate 523 1720 ______________________________________
Table 1 shows the widely differing ability of the various amino acid esters to undergo hydrolysis in human plasma and in buffer.
As will appear from Table 1 the half-life of the 3-dimethylaminopropionate is only slightly shorter in human plasma compared to buffer and whereas the half-life of the 4-dimethylaminobutyrate is relatively much shorter in plasma than in buffer t.sub.1/2 in plasma is still so long that the 4-dimethylaminobutyrate is unsuited as a prodrug of metronidazole. The same applies to the 4-methyl-1-piperazinoacetate and 3-aminopropionate. The esters derived from N,N-dimethylglycine and N-propylglycine have short half-lives in plasma, and consequently these compounds appear to be suitable candidates as prodrugs of metronidazole.
Selection of the optimum prodrug derivative should take into account several other criteria such as the in vitro stability in bulk form and in aqueous solution, toxicity of both the prodrug and the aminoacid moiety released from the derivative, and the ease of synthesis and purification. Based on these criteria the N,N-dimethylglycine ester of metronidazole and acid addition salts thereof have been found to be very suitable prodrugs of metronidazole.